US2026078131A1PendingUtilityA1
Pyrrolo-pyridazine inhibitors of jak2
Est. expirySep 6, 2044(~18.1 yrs left)· nominal 20-yr term from priority
C07D 519/00C07D 498/22C07B 59/002A61P 35/00C07D 487/14
56
PatentIndex Score
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Cited by
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Claims
Abstract
The present disclosure provides pyrrolo-pyridazine compounds and compositions thereof useful for inhibiting JAK2. In some embodiments, the present disclosure provides a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , and R 4 are as defined in classes and subclasses herein, both singly and in combination.
Claims
exact text as granted — not AI-modified1 . A compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen or optionally substituted C 1 -C 6 aliphatic;
R 2 is C 3 -C 12 cycloaliphatic, C 1 -C 6 aliphatic, 2- to 10-membered heteroaliphatic, 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or C 6 -C 10 aryl, wherein R 2 is optionally substituted with one or more instances of -L-R 5 or R 7 ;
each L is independently selected from the group consisting of a bond, —N(R a )C(O)N(R a )—, —N(R a )C(O)O—, —OC(O)N(R a )—, —C(O)N(R a )—, —N(R a )C(O)—, —N(R a )—, —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R a )C(S)O—, —OC(S)N(R a )—, —C(S)N(R a )—, —N(R a )C(S)—, —C(S)—, —C(S)O—, and —OC(S)—;
each R 5 is independently selected from the group consisting of optionally substituted C 1 -C 6 aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, optionally substituted C 3 -C 12 cycloaliphatic, optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted C 6 -C 10 aryl;
each R 7 is independently selected from the group consisting of halogen, —OH, —SH, and —NH 2 ;
R 3 is 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, C 6 -C 12 aryl, C 3 -C 12 cycloaliphatic, or C 1 -C 6 aliphatic, wherein R 3 is optionally substituted with one or more instances of R 3a ; or
R 2 and R 3 are connected by *-L a -R 6 -L b -**, wherein * represents a point of attachment to R 2 , and ** represents a point of attachment to R 3 ;
L a is a bond, —N(R a )C(O)N(R a )—, —N(R a )C(O)O—, —OC(O)N(R a )—, —C(O)N(R a )—, —N(R a )C(O)—, —N(R a )—, —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R a )C(S)O—, —OC(S)N(R a )—, —C(S)N(R a )—, —N(R a )C(S)—, —C(S)—, —C(S)O—, or —OC(S)—;
L b is a bond, —N(R a )C(O)N(R a )—, —N(R a )C(O)O—, —OC(O)N(R a )—, —C(O)N(R a )—, —N(R a )C(O)—, —N(R a )—, —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R a )C(S)O—, —OC(S)N(R a )—, —C(S)N(R a )—, —N(R a )C(S)—, —C(S)—, —C(S)O—, or —OC(S)—;
R 6 is optionally substituted C 1 -C 6 aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, optionally substituted C 3 -C 12 cycloaliphatic, optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or optionally substituted C 6 -C 10 aryl;
R 4 is C 1 -C 6 aliphatic, —CN, 2- to 10-membered heteroaliphatic, C 3 -C 12 cycloaliphatic, 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or C 6 -C 10 aryl, wherein R 4 is optionally substituted with one or more instances of R 4a ;
each R 3a is independently selected from the group consisting of optionally substituted C 1 -C 6 aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, optionally substituted C 3 -C 12 cycloaliphatic, optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted C 6 -C 10 aryl, halogen, oxo, —CN, —NO 2 , —C(O)N(R a ) 2 , —OC(O)R a , —OC(O)N(R a ) 2 , —N(R a )C(O)R a , —N(R a )C(O)OR a , —N(R a )C(O)N(R a ) 2 , —S(O) 2 N(R a ) 2 , —N(R a )S(O) 2 R a , —S(O) 2 R a , and —OR a ;
each R 4a is independently selected from the group consisting of optionally substituted C 1 -C 6 aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, optionally substituted C 3 -C 12 cycloaliphatic, optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted C 6 -C 10 aryl, halogen, oxo, —CN, —NO 2 , —C(O)R a , —C(O)N(R a ) 2 , —OC(O)R a , —OC(O)N(R a ) 2 , —N(R a )C(O)R a , —N(R a )C(O)OR a , —N(R a )C(O)N(R a ) 2 , —S(O) 2 N(R a ) 2 , —N(R a )S(O) 2 R a , —S(O) 2 R a , and —OR a ; and
each R a is independently selected from hydrogen, optionally substituted C 1 -C 6 aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.
2 . (canceled)
3 . The compound of claim 1 , wherein R 1 is optionally substituted C 1 -C 6 aliphatic.
4 - 5 . (canceled)
6 . The compound of claim 1 , wherein R 2 is C 3 -C 7 monocyclic cycloaliphatic or 4- to 6-membered monocyclic heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S; and wherein R 2 is substituted with 1-2 instances of -L-R 5 or R 7 .
7 - 9 . (canceled)
10 . The compound of claim 1 , wherein R 2 is:
11 . (canceled)
12 . The compound of claim 1 , wherein each L is independently selected from a bond, —N(R a )C(O)O—, —OC(O)N(R a )—, —C(O)N(R a )—, —N(R a )C(O)—, —O—, and —C(O)—.
13 . (canceled)
14 . The compound of claim 1 , wherein each R 5 is independently selected from optionally substituted C 1 -C 6 aliphatic, optionally substituted C 3 -C 6 cycloaliphatic, optionally substituted 4- to 6-membered heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S, and optionally substituted 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.
15 . The compound of claim 1 , wherein each -L-R 5 is independently selected from: —CH 3 , —CH 2 OH, —CH 2 OCH 3 ,
16 . (canceled)
17 . The compound of claim 1 , wherein R 2 optionally substituted with one or more -L-R 5 or R 7 is selected from:
18 . The compound of claim 1 , wherein R 3 is 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 9- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, or phenyl, wherein R 3 is optionally substituted with 0-3 instances of R 3a .
19 - 24 . (canceled)
25 . The compound of claim 1 , wherein each R 3a is independently selected from optionally substituted C 1 -C 6 aliphatic, optionally substituted C 3 -C 6 cycloaliphatic, halogen, —C(O)N(R a ) 2 , and —OR a .
26 . The compound of claim 1 , wherein R 3 optionally substituted with one or more instances of R 3a is:
27 - 32 . (canceled)
33 . The compound of claim 1 , wherein R 4 is 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S or 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R 4 is optionally substituted with 0-3 instances of R 4a .
34 - 36 . (canceled)
37 . The compound of claim 1 , wherein each R 4a is independently selected from optionally substituted C 1 -C 6 aliphatic, —OR a , and halogen.
38 . The compound of claim 1 , wherein R 4 optionally substituted with one or more instances R 4a is selected from:
39 - 40 . (canceled)
41 . The compound of claim 1 , wherein the compound is represented by formula IV-2 or IV-3:
or a pharmaceutically acceptable salt thereof.
42 - 43 . (canceled)
44 . The compound of claim 1 , wherein the compound is represented by formula VII-1, VII-2, VII-3, VII-4, or VII-5:
or a pharmaceutically acceptable salt thereof.
45 . (canceled)
46 . The compound of claim 1 , wherein the compound is represented by formula IX:
or a pharmaceutically acceptable salt thereof,
wherein R 5 is optionally substituted cyclopropyl.
47 . A compound selected from:
No.
Structure
I-1
I-1′
I-2
I-2′
I-3
I-3′
I-4-1
I-4-2
I-4′
I-5
I-5′
I-6
I-6′
I-7
I-7′
I-8
I-8′
I-9
I-9′
I-10
I-10′
I-11
I-11′
I-12
I-12′
I-13
I-13′
I-14
I-14′
I-15
I-15′
I-16
I-16′
I-17
I-17′
I-18
I-18′
I-19
I-19′
I-20-1
I-20-2
I-20′
I-21
I-21′
I-22
I-22′
I-23
I-23′
I-24
I-24′
I-25
I-25′
I-26
I-26′
I-27
I-27′
I-28
I-28′
I-29
I-29′
I-30
I-30′
I-31
I-31′
I-32
I-32′
I-33
I-33′
I-34
I-34′
I-35
I-35′
I-36
I-36′
I-37-1
I-37-2
I-37′
I-38
I-38′
I-40
I-40′
I-41
I-41′
I-42
I-42′
I-43
I-43′
I-44
I-44′
I-45
I-45′
I-46
I-46′
I-47
I-47′
I-48
I-48′
I-49
I-49′
I-50
I-50′
I-51
I-51′
I-52
I-52′
I-53
I-53′
I-54
I-54′
I-55
I-55′
I-56
I-56′
I-57
I-57′
I-58
I-58′
I-59
I-59′
I-60
I-60′
I-61
I-61′
I-62
I-62′
I-63
I-63′
I-64
I-64′
I-65
I-65′
I-66
I-66′
I-67
I-67′
I-68
I-68′
I-69
I-69′
I-70
I-70′
I-71
I-71′
I-72
I-72′
I-73
I-73′
I-74
I-74′
I-75
I-75′
I-76
I-76′
I-77
I-77′
I-78
I-78′
I-79
I-79′
I-80
I-80′
I-81
I-81′
I-82
I-82′
I-83
I-83′
I-84
I-84′
I-85
I-85′
I-86
I-86′
I-87
I-87′
I-88
I-88′
I-89
I-89′
I-90
I-90′
I-91
I-91′
I-93
I-93′
I-94
I-94′
I-95
I-95′
I-96
I-96′
I-97
I-97′
I-98
I-98′
I-99
I-99′
I-100
I-100′
I-101
I-101′
I-102
I-102′
I-103
I-103′
I-104
I-104′
I-105
I-105′
I-106
I-106′
I-107
I-107′
I-108
I-108′
I-109
I-109′
I-110
I-110′
I-111
I-111′
I-112
I-112′
I-113
I-113′
I-114
I-114′
I-115
I-115′
I-116
I-116′
I-117
I-117′
I-118
I-118′
I-119
I-119′
I-120
I-120′
I-121
I-121′
I-122
I-122′
I-123
I-123′
I-124
I-124′
I-125
I-125′
I-126
I-126′
I-127
I-127′
I-128
I-128′
I-129
I-129′
I-130
I-130′
I-131
I-131′
I-132
I-132′
I-133
I-133′
I-134
I-134′
I-135
I-135′
I-136
I-136′
I-137
I-137′
I-138
I-138′
I-139
I-139′
I-140
I-140′
I-141
I-141′
I-142
I-142′
I-143
I-143′
I-144
I-144′
I-145
I-145′
I-146
I-146′
I-147
I-147′
I-148
I-148′
I-149
I-149′
I-150
I-150′
I-151
I-151′
I-152
I-152′
I-153
I-153′
I-154
I-154′
I-155
I-155′
I-156
I-156′
I-157
I-157′
I-158
I-158′
I-159
I-159′
I-160
I-160′
I-161
I-161′
I-162
I-162′
I-163
I-163′
I-164
I-164′
I-165
I-165′
I-166-1
I-166-2
I-166′
I-167
I-167′
I-168
I-168′
I-169
I-169′
I-170
I-170′
I-171
I-171′
I-172
I-172′
I-173
I-173′
I-174
I-174′
I-175
I-175′
I-176
I-176′
I-177
I-177′
I-178
I-178′
I-179-1
I-179-2
I-179′
I-180
I-180′
I-181
I-181′
I-182
I-182′
I-183
I-183′
I-184
I-184′
I-185
I-185′
I-186
I-186′
I-187
I-187′
I-188
I-188′
I-189
I-189′
I-190
I-190′
I-191
I-191′
I-192
I-192′
I-193
I-193′
I-194
I-194′
I-195
I-195′
I-196
I-196′
I-197
I-197′
I-198
I-198′
I-199
I-199′
I-200
I-200′
I-201
I-201′
I-202
I-202′
I-203
I-203′
I-204
I-204′
I-205
I-205′
I-206
I-206′
I-207
I-207′
I-208
I-208′
I-209
I-209′
I-210
I-210′
I-211
I-211′
I-212
I-212′
I-213
I-213′
I-214
I-214′
I-215
I-215′
I-216
I-216′
I-217
I-217′
I-218
I-218′
I-219
I-219′
I-220
I-220′
I-221
I-221′
I-222
I-222′
I-223
I-223′
I-224
I-224′
I-225
I-225′
I-226
I-226′
I-227
I-227′
I-228
I-228′
I-229
I-229′
I-230
I-230′
I-231
I-231′
I-232
I-232′
I-233
I-233′
I-234
I-234′
I-235
I-235′
I-236
I-236′
I-237
I-237′
I-238
I-238′
I-239
I-239′
I-240
I-240′
I-241
I-241′
I-242
I-242′
I-243-1
I-243-2
I-243′
I-244
I-244′
I-245
I-245′
I-246-1
I-246-2
I-246′
I-247
I-247′
I-248
I-248′
I-249
I-249′
I-250
I-250′
I-251
I-251′
I-252-1
I-252-2
I-252′
I-253
I-253′
I-254
I-254′
I-255
I-255′
I-256
I-256′
I-257
I-257′
I-258
I-258′
I-259
I-259′
I-260
I-260′
I-261
I-261′
I-262-1
I-262-2
I-262′
I-263
I-263′
I-264
I-264′
I-265
I-265′
I-266
I-266′
I-267
I-267′
I-268
I-268′
I-269
I-269′
I-270
I-270′
I-271
I-271′
I-272
I-272′
I-273
I-273′
I-274
I-274′
I-275
I-275′
I-276
I-276′
I-277
I-277′
I-278
I-278′
I-279
I-279′
I-280
I-280′
I-281
I-281′
I-282-1
I-282-2
I-282′
I-283-1
I-283-2
I-283′
I-284
I-284′
I-285
I-285′
I-286
I-286′
I-287
I-287′
I-288
I-288′
I-289
I-289′
I-290
I-290′
I-291
I-291′
I-292
I-292′
I-293
I-293′
I-294
I-294′
I-295
I-295′
I-296
I-296′
I-297-1
I-297-2
I-297′
I-298
I-298′
I-299-1
I-299-2
I-299′
I-300-1
I-300-2
I-300′
I-301-1
I-301-2
I-301′
I-302
I-302′
I-303-1
I-303-2
I-303′
I-304-1
I-304-2
I-304′
I-305
I-305′
I-306
I-306′
I-307
I-307′
I-308
I-308′
I-309
I-309′
I-310-1
I-310-2
I-310′
I-311
I-311′
I-312
I-312′
I-313
I-313′
I-314
I-314′
I-315
I-315′
I-316
I-316′
I-317
I-317′
I-318
I-318′
I-319
I-319′
I-320
I-320′
I-321-1
I-321-2
I-321′
I-322
I-322′
I-323
I-323′
I-324
I-324′
I-325
I-325′
I-326-1
I-326-2
I-326′
I-327
I-327′
I-328
I-328′
I-329-1
I-329-2
I-329′
I-330-1
I-330-2
I-330′
I-331
I-331′
I-332
I-332′
I-333
I-333′
I-334
I-334′
I-335
I-335′
I-336
I-336′
I-337
I-337′
I-338
I-338′
I-339
I-339′
I-340
I-340′
I-341-1
I-341-2
I-341′
I-342-1
I-342-2
I-342′
I-343-1
I-343-2
I-343′
I-344
I-344′
I-345
I-345′
I-346
I-346′
I-347-1
I-347-2
I-347′
I-348-1
I-348-2
I-348′
I-349-1
I-349-2
I-349′
I-350
I-350′
I-351-1
I-351-2
I-351′
I-352-1
I-352-2
I-352′
I-353
I-353′
I-354
I-354′
I-355
I-355′
I-356
I-356′
I-357
I-357′
I-358
I-358′
I-359
I-359′
I-360
I-360′
I-361
I-361′
I-362
I-362′
I-363
I-363′
I-364
I-364′
I-365
I-365′
I-366
I-366′
I-367
I-367′
I-368
I-368′
I-369
I-369′
I-370-1
I-370-2
I-370′
I-371-1
I-371-2
I-371′
I-372
I-372′
I-373
I-373′
I-374
I-374′
I-375
I-375′
I-376
I-376′
I-377-1
I-377-2
I-377′
I-378
I-378′
I-379
I-379′
I-380
I-380′
I-381
I-381′
or a pharmaceutically acceptable salt thereof.
48 . A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
49 . A method of inhibiting JAK2 in a subject, comprising administering to the subject the compound of claim 1 .
50 . A method of treating a disease, disorder, or condition associated with JAK2, comprising administering to a subject in need thereof the compound of claim 1 .
51 . A method of treating cancer, comprising administering to a subject in need thereof the compound of claim 1 .
52 . A method of treating a hematological malignancy, comprising administering to a subject in need thereof the compound of claim 1 .
53 . (canceled)
54 . A method of treating a myeloproliferative neoplasm, comprising administering to a subject in need thereof the compound of claim 1 .
55 . The method of claim 54 , wherein the myeloproliferative neoplasm is polycythemia vera, essential thrombocytopenia, or myelofibrosis.Join the waitlist — get patent alerts
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